Identification of biologically active δ-lactone eicosanoids as paraoxonase substrates

John F. Teiber, Junhui Xiao, Gerald L. Kramer, Seiji Ogawa, Christian Ebner, Helene Wolleb, Erick M. Carreira, Diana M. Shih, Robert W. Haley

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.

Original languageEnglish (US)
Pages (from-to)87-92
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume505
Issue number1
DOIs
StatePublished - Oct 20 2018

Fingerprint

Aryldialkylphosphatase
Eicosanoids
Lactones
Substrates
Acids
Liver
Esterases
Structure-Activity Relationship
Unsaturated Fatty Acids
Arachidonic Acid
Knockout Mice
Edetic Acid
Hydrolysis
Anti-Inflammatory Agents
Antioxidants
Lipids

Keywords

  • Eicosanoid
  • Esterase
  • Isoprostanes
  • Lactone
  • Paraoxonase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Identification of biologically active δ-lactone eicosanoids as paraoxonase substrates. / Teiber, John F.; Xiao, Junhui; Kramer, Gerald L.; Ogawa, Seiji; Ebner, Christian; Wolleb, Helene; Carreira, Erick M.; Shih, Diana M.; Haley, Robert W.

In: Biochemical and Biophysical Research Communications, Vol. 505, No. 1, 20.10.2018, p. 87-92.

Research output: Contribution to journalArticle

Teiber, John F. ; Xiao, Junhui ; Kramer, Gerald L. ; Ogawa, Seiji ; Ebner, Christian ; Wolleb, Helene ; Carreira, Erick M. ; Shih, Diana M. ; Haley, Robert W. / Identification of biologically active δ-lactone eicosanoids as paraoxonase substrates. In: Biochemical and Biophysical Research Communications. 2018 ; Vol. 505, No. 1. pp. 87-92.
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AU - Teiber, John F.

AU - Xiao, Junhui

AU - Kramer, Gerald L.

AU - Ogawa, Seiji

AU - Ebner, Christian

AU - Wolleb, Helene

AU - Carreira, Erick M.

AU - Shih, Diana M.

AU - Haley, Robert W.

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AB - The mammalian paraoxonases (PONs 1, 2 and 3) are a family of esterases that are highly conserved within and between species. They exhibit antioxidant and anti-inflammatory activities. However, their physiological function(s) and native substrates are uncertain. Previous structure-activity relationship studies demonstrate that PONs have a high specificity for lipophilic lactones, suggesting that such compounds may be representative of native substrates. This report describes the ability of PONs to hydrolyze two bioactive δ-lactones derived from arachidonic acid, 5,6-dihydroxy-eicosatrienoic acid lactone (5,6-DHTL) and cyclo-epoxycyclopentenone (cyclo-EC). Both lactones were very efficiently hydrolyzed by purified PON3. PON1 efficiently hydrolyzed 5,6-DHTL, but with a specific activity about 15-fold lower than PON3. 5,6-DHTL was a poor substrate for PON2. Cyclo-EC was a poor substrate for PON1 and not hydrolyzed by PON2. Studies with the PON inhibitor EDTA and a serine esterase inhibitor indicated that the PONs are the main contributors to hydrolysis of the lactones in human and mouse liver homogenates. Studies with homogenates from PON3 knockout mouse livers indicated that >80% of the 5,6-DHTL and cyclo-EC lactonase activities were attributed to PON3. The findings provide further insight into the structural requirements for PONs substrates and support the hypothesis that PONs, particularly PON1 and PON3, evolved to hydrolyze and regulate a class of lactone lipid mediators derived from polyunsaturated fatty acids.

KW - Eicosanoid

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KW - Isoprostanes

KW - Lactone

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